1. Field of the Invention
The present invention concerns probes for the determination of the proclivity in human individuals to develop autoimmune diseases, particularly insulin-dependent diabetes mellitus (IDDM).
2. Background Information
Diabetes mellitus (DM) a syndrome characterized by insufficient insulin secretion, hyperglycermia and a propensity to develop universal microargiopathy, neuropathy and atherosclerosis, is a common condition affecting 1 to 2 per cent of Caucasian populations Insulin-dependent diabetes mellitus (IDDM) (Type 1 diabetes) comprises 10 to 15 per cent of all DM sufferers and is characterized by a selective pancreatic beta cell destruction, a very low, if any, insulin secretion, an absolute requirement for exogenous insulin, a low age of onset (although cases do occur in all ages) and a high percentage of autoantibodies directed against antigenic determinants of the beta-cells. IDDM has been shown to be associated with two alleles (HLA-DR3 and HLA-DR4) of the HLA-D/DR locus on chromosome 6. While these two alleles are present in 97% of IDDM patients, they are also present in 50% of the background population (Caucasian), and, therefore, these markers as serologically defined are not highly specific for the disease.
Essential to an understanding of the etiology of insulin-dependent diabetes mellitus (IDDM) is a more complete definition of the specific genetic susceptibilities. In family studies, the individuals at highest risk for IDDM are siblings who share both HLA haplotypes with the diabetic proband; their lifetime risk for disease is in the order of 12-24% (A. N. Gorsuch, K. M. Spencer, J. Lister, E. Wolf, G. M. Bottazzo and A. G. Cudworth, "Can Future Type 1 Diabetes be Predicted. A Study in Families of Affected Children", Diabetes, 31, 862-866, (1982)). In contrast, the highest population-based absolute risk for IDDM, i.e., that for an individual with both HLA-DR3 and DR4, is only 2-4% (P. Platz, B. K. Jakobsen, N. Morling, L. P. Ryder, A. Svejgaard, J. Thomsen, M. Christy, H. Kromann, J. Benn, J. Nerup, A. Green and M. Hauge, "HLA-D and -DR Antigens in Genetic Analysis of Insulin Dependent Diabetes Mellitus", Diabetologia, 21, 108-115, (1981)); C. Johnston, D. A. Pyke, A. G. Cudworth and E. Wolf, "HLA-DR Typing in Identical Twins with Insulin-Dependent Diabetes: Difference Between Concordant and Discordant Pairs", Br. Med. J., 286, 253-255, (1983); J. I. Rotter, C. M. Vadheim, L. J. Raffel and D. L. Rimoin, "Genetics, Diabetes Mellitus Heterogeneity, and Coronary Heart Disease", D. C. Rao, R. E. Elston, L. H. Kuller, M. Feinlieb, C. Carter and R. Havlik (eds.): The Genetic Epidemiology of Coronary Heart Disease, Alan R. Liss, New York, (1984)). The absolute risks for the remaining predisposing genotypes are considerably lower. If the susceptibility to IDDM is due solely to these DR genes, as currently characterized, then the absolute risk should be similar for family members and persons with identical HLA genotypes in the population. Clearly they are not. This significant difference between the population and family data strongly suggests that HLA-DR3 and DR4, as currently serologically defined, do not themselves cause susceptibility to IDDM and that further work is needed to find markers which truly correlate with the development of IDDM.
According to current knowledge, the HLA-D region consists of at least 13 loci: three DR, two Q, two DP beta genes, and one DZ, one DR, two DQ and two DP alpha genes (F. H. Bach, "The HLA Class II Gene Products: The HLA-D Region", Immunology Today, 6, 89-96, (1985)). D. Owerbach, A. Lernmark, P. Platz, P. Pyder, L. Rask, P. A. Peterson and J. Ludsigsson, "HLA-DR Beta-chain DNA Endonuclease Fragments Differ Between Healthy and Insulin-Dependent Diabetic Individuals", Nature, 303, 815-817, (1983); Haguenauer et al, PNAS, Vol. 82, pp. 3335-3339, (1985); and Arnheim et al, PNAS, Vol. 82, pp. 6970-6974, (1985) have investigated polymorphisms of the HLA-D region using a HLA-DQ beta cDNA probe on DNA from lymphocytes isolated from IDDM patients and controls and report an increased frequence of certain restriction fragments in controls versus HLA-DR matched IDDM patients. While those methods increase the strength of association of HLA markers and IDDM compared with serologic tests, the association is still not specific enough to determine with a high degree of accuracy proclivity in human individuals to develop IDDM.
PCT WO 83/03260 concerns a method for determining tissue types coded by MHC genes.
Canadian Patent 1,186,991 concerns a method for the determination of liability in humans to develop non-insulin-dependent diabetes mellitus (NIDDM).